Signaling by the Matrix Proteoglycan Decorin Controls Inflammation and Cancer Through PDCD4 and MicroRNA-21

Abstract

The mechanisms linking immune responses and inflammation with tumor development are not well understood. Here we show that the soluble form of the extracellular matrix proteoglycan decorin controls inflammation and tumor growth through PDCD4 (programmed cell death 4) and microRNA (miR) 21 by two mechanisms. First, decorin acted as an endogenous ligand of Toll-like receptor-2 and −4 and stimulated production of proinflammatory molecules, including PDCD4, in macrophages. Second, decorin prevented translational repression of PDCD4 by decreasing the activity of transforming growth factor (TGF) β1 and the abundance of oncogenic miR-21, a translational inhibitor of PDCD4. Moreover, increased PDCD4 resulted in decreased release of the anti-inflammatory cytokine interleukin-10, thereby making the cytokine profile more proinflammatory. This pathway operates in both pathogen-mediated and sterile inflammation as shown here for sepsis and growth retardation of established tumor xenografts. In sepsis, decorin is an early response gene evoked by septic inflammation and decorin concentrations were increased in plasma of septic patients and mice. In cancer, decorin mediated the reduced abundance of anti-inflammatory molecules and increased that of pro-inflammatory molecules, thereby shifting the immune response to a more proinflammatory state that was associated with reduced tumor growth. Thus, by stimulating pro-inflammatory PDCD4 and decreasing the abundance of miR-21, decorin signaling boosts inflammatory activity in sepsis and suppresses tumor growth.

Small leucine-rich proteoglycans orchestrate receptor crosstalk during inflammation

“…Decorin is capable of binding to four different receptor tyrosine kinases (RTKs), including the epidermal growth factor receptor (EGFR), 34 insulin-like growth factor-1 receptor (IGF-IR), [35][36][37][38] Met 39 and vascular endothelial growth factor receptor 2 (VEGFR2), 40 thereby impacting on fibrogenesis, 19 tumor growth and metastatic spreading. 12,41,42 A summary of recent data demonstrating the intricacy of decorin signaling, which links innate immunity, inflammation and tumor growth 16 is provided below.…”

“…Upon tissue stress or injury, matrix components will be released and turn into signaling molecules. 12,18,19 Among this large group of ECM components, only a few, such as biglycan, 14 decorin, 16 hyaluronan, 20 versican, 21 tenascin-C, 22 fibrinogen and heparan sulfate fragments, 23 are capable of interacting with PRRs, thereby alerting the innate immune system to impending tissue damage. These mechanisms give rise to a rapid response reaction without the need for de novo synthesis of danger molecules.…”

“…2,13 In this review, the complexity of proinflammatory signaling of the two matrix proteoglycans decorin and biglycan, both acting as DAMPs, [14][15][16] will be addressed. Particular focus will be put on newly described mechanisms of how these molecules orchestrate the interaction of various receptors, which are involved in triggering sterile inflammation.…”

“…Particular focus will be put on newly described mechanisms of how these molecules orchestrate the interaction of various receptors, which are involved in triggering sterile inflammation. 15,16 Decorin-and biglycan-mediated receptor crosstalk involves TLRs, NLRs and transforming growth factor β (TGFβ) receptors and is further fine-tuned by miR-21. 15,16 Thus, we will focus on the multifunctional proinflammatory signaling properties of decorin and biglycan.…”

“…15,16 Decorin-and biglycan-mediated receptor crosstalk involves TLRs, NLRs and transforming growth factor β (TGFβ) receptors and is further fine-tuned by miR-21. 15,16 Thus, we will focus on the multifunctional proinflammatory signaling properties of decorin and biglycan. These two archetypal SLRPs, when released in a soluble form, can link the innate to the adaptive immune response and can operate in a broad biological context, such as microbial defense, tumor growth and autoimmunity.…”